Taxol, 1, a material occurring in nature, and extracted from Taxus brevifolia (i.e., the Pacific yew tree) and other biomass has been identified as having significant tubulin binding (Schiff, P. B. et al., "Promotion of Microtubule Assembly in vitro by Taxol," Nature, Vol. 277:665-67 (February 1979)) and, when delivered to the cell, cytotoxic activity which has been demonstrated through Phase III clinical trials. Taxol was recently approved for the treatment of refractory ovarian cancer by the Food and Drug Administration.
Taxotere, 2, a semisynthetic derivative of taxol with improved water solubility, has been compared with taxol in Phase I clinical trials. Taxotere is slightly more active as a promoter of tubulin polymerization, 1.5-fold more potent as an inhibitor of replication in mouse macrophage-like J774.2 cells and in P388 murine leukemia cells, and at least fivefold more potent in taxol resistant tumor cells (Pazdur, R. et al., "Phase I Trial of Taxotere: Five-Day Schedule", Journal of the National Cancer Institute, 1781, (1992)). The structural differences between taxol 1 and taxotere 2 are minor (see FIG. 1), yet enhanced in vitro tubulin binding activity is observed for taxotere.
Consequently, it is difficult to predict the relative potency of a taxol analogue for microtubulin polymerization activity based on small changes in the overall structure. An examination of Kingston's Review, (Kingston, D. G. I., "The Chemistry of Taxol", Pharmacology and Therapeutics, 52:1-34, (1991)), provides an overall view of the complexity of the structure-activity relationship of taxol analogues. It is clear that minor structural changes can cause major changes in tubulin binding activity and cytotoxicity. These changes can even completely eliminate activity. In addition, other factors such as greater water solubility and lower toxicity exist, which must be strongly considered when evaluating the efficacious nature of therapeutic agents.
The novel synthetic taxol derivatives described herein have not heretofore been described nor has the literature suggested that such new derivatives would exhibit tubulin assembly or advantageous cytotoxic activity.